17-31226456-G-A
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BP4_ModerateBP6BS2_Supporting
The NM_001042492.3(NF1):c.2023G>A(p.Gly675Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
NF1
NM_001042492.3 missense
NM_001042492.3 missense
Scores
10
9
Clinical Significance
Conservation
PhyloP100: 4.39
Genes affected
NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ: 6.5427 (greater than the threshold 3.09). Trascript score misZ: 8.4054 (greater than threshold 3.09). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. GenCC has associacion of the gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.
BP4
Computational evidence support a benign effect (MetaRNN=0.17707059).
BP6
Variant 17-31226456-G-A is Benign according to our data. Variant chr17-31226456-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 230614.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}. Variant chr17-31226456-G-A is described in Lovd as [Benign].
BS2
High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 151962Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250548Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135406
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461522Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727072
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GnomAD4 genome 0.0000197 AC: 3AN: 151962Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74222
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:2Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 06, 2025 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 02, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Neurofibromatosis, familial spinal Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 02, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Neurofibromatosis-Noonan syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 02, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed among unaffected controls, but not in any cases in a breast cancer study (Momozawa 2018); This variant is associated with the following publications: (PMID: 30287823, 25486365) - |
Café-au-lait macules with pulmonary stenosis Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 02, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Hereditary cancer-predisposing syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 13, 2015 | Thep.G675Rvariant (also known as c.2023G>A), located in coding exon 18 of theNF1gene, results from a G to A substitution at nucleotide position 2023. The glycine at codon 675 is replaced by arginine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 55000 alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance of p.G675Rremains unclear. - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 19, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Uncertain
D;D;T
Sift4G
Uncertain
D;D;D
Polyphen
P;P;.
Vest4
MutPred
Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);.;
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at